与骨关节炎患者相比，类风湿关节炎患者中神经递质对滑膜成纤维细胞白细胞介素6（IL-6）和白细胞介素8分泌的调节作用

Neurotransmitter modulation of interleukin 6 (IL-6) and IL-8 secretion of synovial fibroblasts in patients with rheumatoid arthritis compared to osteoarthritis.

作者信息

Raap T, Jüsten H P, Miller L E, Cutolo M, Schölmerich J, Straub R H

机构信息

Department of Internal Medicine I, University Medical Center Regensburg, Germany.

出版信息

J Rheumatol. 2000 Nov;27(11):2558-65.

PMID:11093434

Abstract

OBJECTIVE

The sensory nervous system with the 2 neurotransmitters substance P (SP) and calcitonin gene related peptide (CGRP) is proinflammatory in experimental models of arthritis. The role of the sympathetic nervous system with norepinephrine (NE), adenosine, beta-endorphin, and methionine enkephalin (MENK) is not clearly understood. We studied the influence of these neurotransmitters on secretion of interleukin 6 (IL-6) and IL-8 in primary cultures of synovial fibroblasts of patients with rheumatoid arthritis (RA) compared to osteoarthritis (OA).

METHODS

Fibroblasts were isolated using fresh synovial tissue of 5 patients with RA and 5 with OA who underwent knee joint replacement surgery. Modulation of spontaneous secretion of IL-6 and IL-8 was investigated in vitro using the neurotransmitters noted above.

RESULTS

In RA fibroblasts, CGRP increased IL-6 and IL-8 secretion at 10(-10) to 10(-8) M (p at least < 0.01), which was not observed in OA fibroblasts. SP had no effect on either cytokine in RA fibroblasts but stimulated IL-8 secretion at 10(-8) M in OA fibroblasts (p < 0.01). In RA fibroblasts, adenosine and NE inhibited secretion of both cytokines at low concentrations (10(-8) M; p < 0.01). However, in OA fibroblasts there was a NE induced increase of IL-8 and IL-6 secretion at 10(-7) and 10(-6) M (p < 0.01), but no inhibition at lower concentrations (10(-8) M; p = NS). In RA fibroblasts, beta-endorphin and MENK inhibited IL-8 secretion at 10(-9) to 10(-7) M (p < 0.01), whereas in OA fibroblasts the dose response curve was shifted to lower concentrations (10(-12) M, 10(-11) M; p < 0.01).

CONCLUSION

In OA fibroblasts, the sympathetic neurotransmitters were stimulatory at higher concentrations. CGRP was the most potent stimulatory neurotransmitter in RA fibroblasts whereas the sympathetic adenosine, NE, beta-endorphin, and MENK were inhibitory. This indicates a dualism of action of sympathetic and sensory neurotransmitters, with inhibitory and stimulatory effects on cytokine secretion of RA fibroblasts.

摘要

目的

在关节炎实验模型中，含有两种神经递质即P物质（SP）和降钙素基因相关肽（CGRP）的感觉神经系统具有促炎作用。而含有去甲肾上腺素（NE）、腺苷、β-内啡肽和甲硫氨酸脑啡肽（MENK）的交感神经系统的作用尚不清楚。我们研究了这些神经递质对类风湿关节炎（RA）患者与骨关节炎（OA）患者滑膜成纤维细胞原代培养物中白细胞介素6（IL-6）和IL-8分泌的影响。

方法

使用5例接受膝关节置换手术的RA患者和5例OA患者的新鲜滑膜组织分离成纤维细胞。使用上述神经递质在体外研究对IL-6和IL-8自发分泌的调节作用。

结果

在RA成纤维细胞中，CGRP在10⁻¹⁰至10⁻⁸M时增加IL-6和IL-8分泌（p至少<0.01），而在OA成纤维细胞中未观察到这种情况。SP对RA成纤维细胞中的两种细胞因子均无影响，但在10⁻⁸M时刺激OA成纤维细胞分泌IL-8（p<0.01）。在RA成纤维细胞中，腺苷和NE在低浓度（10⁻⁸M；p<0.01）时抑制两种细胞因子的分泌。然而，在OA成纤维细胞中，NE在10⁻⁷和10⁻⁶M时诱导IL-8和IL-6分泌增加（p<0.01），但在较低浓度（10⁻⁸M；p=无统计学意义）时无抑制作用。在RA成纤维细胞中，β-内啡肽和MENK在10⁻⁹至I0⁻⁷M时抑制IL-8分泌（p<0.01），而在OA成纤维细胞中，剂量反应曲线向较低浓度（10⁻¹²M，10⁻¹¹M；p<0.01）偏移。